Management of uterine fibroids in the patient pursuing assisted reproductive technologies

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1 Review Management of uterine fibroids in the patient pursuing assisted reproductive technologies Mohammad Ezzati, John M Norian & James H Segars Uterine leiomyomas are present in 30 70% of women of reproductive age. In addition to causing menstrual disorders and pain, uterine fibroids negatively affect fertility and pregnancy outcome for patients pursuing assisted reproduction. The two questions that have to be addressed are: which fibroids should be treated and how should they be treated? Submucosal fibroids are associated with a 70% reduction in delivery rate. Intramural fibroids had a lesser effect and reduced the delivery rate by approximately 30%. By contrast, studies have demonstrated that subserosal fibroids did not negatively impact fertility. Furthermore, both submucosal and intramural fibroids were associated with an increased risk of spontaneous miscarriage. Myomectomy is considered the treatment of choice to alleviate these detrimental effects. Further research is needed before alternative treatments can be recommended. Uterine leiomyomas (also termed fibroids and myomas) are exceedingly common. The prevalence of fibroids is defined as 77% by pathologic examination of hysterectomy specimens [1]. Fortunately, many fibroids are asymptomatic. Depending on the methods used to detect fibroid tumors, the reported prevalence ranged from 30 to 70% [1 5]. The prevalence is increased in women of African American ethnicity. The incidence of fibroids also increases as women age. A large study evaluating 1364 randomly selected women aged years in an urban setting in the USA, reported an estimated cumulative incidence of fibroids by age 50 years of more than 80% for Black women and nearly 70% for White women [3]. Uterine fibroids often cause menstrual disorders, mainly menorrhagia, as well as pelvic pressure and/or pain. In addition, acute abdominal pain can arise from the degeneration of fibroids [6,7]. Likewise, it is clear that fibroids can adversely affect the reproductive outcome. The adverse effects include both a reduction in fertility and an association with early pregnancy complications [8 21]. Furthermore, studies have shown that fibroids can contribute to adverse obstetric outcomes, such as preterm labor and delivery, placenta previa, intrauterine growth retardation, increased rate of cesarean section and postpartum hemorrhage [22 27]. Considering the significant health burden fibroids pose to women, development of appropriate evidencebased management strategies for uterine fibroids, addressing both efficacy and safety, is of crucial importance. In this review, we focus on the specific question of the impact of fibroids on fertility in general, and assisted reproductive technology (ART) outcome in particular. Regardless of their location, size, or number, uterine fibroids are found in approximately 5 10% of women with infertility [28 30]. For approximately % of women with infertility, fibroids are the only abnormal finding [28 30]. Many hypotheses have been proposed to explain the possible detrimental effect of fibroids on fertility, including impaired and/or obstructed gamete transport [28], dysfunctional uterine contractility [28,33], altered endometrial receptivity [34], abnormal vascularization [28,34], chronic inflammation and abnormal hormonal milieu [28,34]. For women undergoing ART, it is reasonable to conclude that altered endometrial receptivity is involved since other proposed mechanisms are bypassed by ART. The adverse endometrial effects of fibroids have been known for more than 30 years. The glandular atrophy in the endometrium overlying the fibroid is one of the most commonly observed histological alterations associated with fibroids [34,35]. In addition, existing evidence indicates that these effects are directly dependent on the proximity of the fibroid to the endometrium [36]. Furthermore, histologic changes have been noted on the endometrial surface opposite the fibroid, which might be attributed to the mechanical pressure exerted by the fibroids [36]. More recently, experiments by Rackow and Taylor have demonstrated that the presence of submucosal and intramural Author for correspondence: Reproductive Biology & Medicine Branch, NICHD, NIH, Building 10, CRC, 1 East, Room , 10 Center Drive, Bethesda, MD 20892, USA Tel.: Fax: segarsj@mail.nih.gov Keywords ART fibroids implantation rate infertility myomectomy pregnancy rate part of /WHE Future Medicine Ltd Women's Health (2009) 5(4), ISSN

2 Review Ezzati, Norian & Segars fibroids results in a global reduction in endometrial HOX gene expression, which is not limited to the focal area overlying the fibroid(s) [37]. The authors suggested the observed impaired endometrial receptivity might be mediated by a diffusible signaling molecule(s) that is secreted from the fibroid, but exerts its effects across the entire endometrium. Classification & diagnosis At present there is no universally accepted classification system for fibroids and this has limited the research into their effects on fertility outcome. Fibroids are typically classified based on their location as submucosal, intramural and subserosal [8,38,39]. Considering that there is no mucosal epithelium in the uterus, the term submucosal is a misnomer; the more appropriate name is subendometrial but the term submucosal has been widely used in literature. A broad definition is that submucosal fibroids are those that distort the endometrial cavity; however, submucosal fibroids can be further subdivided into three subtypes: type 0, pedunculated fibroids without any intramural extension; type I, sessile with less than 50% intramural extension; and type II, sessile with more than 50% intramural extension [38]. Intramural fibroids by definition do not distort the endometrial cavity and less than 50% of their largest diameter protrudes into the serosal surface of the uterus. Subserosal fibroids, similar to intramural fibroids, do not distort the endometrial cavity, but more than 50% of the fibroid extends beyond the serosal surface of the uterus. Subserosal fibroids can be either sessile or pedunculated [8,38,39]. One major limitation of the current classification is that it does not take into account the size of the fibroids. Considering that the thickness of normal myometrium is typically only mm [12], based on this classification, any fibroid larger than 4 cm that does not distort the uterine cavity would be classified as subserosal, even though it might be present in the entire thickness of the myometrium. A new classification system that takes into account location and size of uterine fibroids is under development at the NIH and may help in the assessment of the effect of fibroids on fertility. The two most commonly used modalities to evaluate the effects of fibroids on the uterine cavity are hysterosalpingogram and transvaginal ultrasonography. The sensitivity and specificity of hysterosalpingogram for detection of intrauterine lesions may be as low as 50 and 20%, respectively [40 44]. Transvaginal ultrasound was initially considered to have a sensitivity as high as % and a specificity of 87 98% [45 48]. However, subsequent studies failed to reproduce the initial reports and showed sensitivities as low as 69% [49 55] and a specificity of 11% for accurate identification of submucosal fibroids [56]. More recently, saline infusion sonography or sonohysterography, particularly the 3D mode, has gained popularity as an accurate imaging modality for the evaluation of uterine cavity [56 58]. Hysteroscopy is considered the gold standard for the evaluation of uterine cavity. Compared with hysteroscopy, 2D and 3D sonohysterography have sensitivities of 98 and 100%, respectively [58]. More importantly, 2D and 3D sonohysterography are reported to have specificities of 100%. By contrast, the specificity of transvaginal ultrasonography can be as low as 11% when compared with hysteroscopy or 3D sonohysterogram [56 58]. In addition to hysteroscopy, MRI is another reliable diagnostic modality that may accurately identify and localize the fibroids, especially in complicated cases. Since it is expensive, MRI is usually performed as an ancillary imaging method [54,59]. Obviously, the method(s) used by investigators to ascertain the presence of fibroids may affect which subjects are diagnosed to have fibroids and could affect the studies conclusions. Fibroids & infertility Published reports of the effect of fibroids on reproductive outcome and fertility may be confusing or even contradictory. The contradictory findings can be explained in part by the lack of appropriate control groups, inconsistent evaluation of the uterine cavity, the imaging method used to diagnose fibroids or insufficient number of subjects (small sample size). An additional point is that pregnancy is multifactorial and variables other than fibroids contribute to fertility. Time to pregnancy is affected by these other variables, and the existence of these confounding variables may contribute to different outcomes across studies. ART provides unique advantages in analyzing the effects of fibroids on fertility because the tightly controlled nature of the procedures helps to mitigate the confounding effects of time to pregnancy, and other variables such as sperm concentration and tubal transport. There are numerous studies investigating the ART outcome in women with fibroids [60 74]. From these studies, and recent systematic reviews and meta-analyses, definitive conclusions can be drawn regarding the effects of fibroids on ART success future science group

3 Management of uterine fibroids in the patient pursuing assisted reproductive technologies Review Submucosal fibroids For fibroids that distort the cavity there is consensus of a negative impact on both the clinical pregnancy rate and delivery rate with odds ratio (OR) at 0.3 (95% CI for clinical pregnancy rate: ; 95% CI for delivery rate: ) [9 14]. In addition, studies have also reported an increased risk of spontaneous miscarriage with submucosal fibroids. One study reported an OR of 3.8 (95% CI: ) [13] and the other an OR of 1.6 (95% CI: ) [14]. Furthermore, with the presence of submucosal fibroids, there is good evidence that myomectomy can improve fertility in general, and IVF outcome in particular. Intramural fibroids The effect of intramural fibroids (those not distorting the uterine cavity) on reproductive outcome was unclear until recently. In 1995, Farhi et al. did not find a detrimental effect for fibroids that did not affect the uterine cavity [60]. However, in 1998, two separate groups, Eldar- Geva et al. [61] and Stovall et al. [62], reported a reduced pregnancy rate and implantation rate in women with intramural fibroids, even in the absence of cavity distortion. Subsequent studies were inconsistent, with some supporting a negative effect of intramural fibroids [64,66,73] while the others did not show an effect on the ART outcome [65,67,68,70,71,74]. The disparate findings of these studies have been resolved in recent years. Benecke et al. conducted a structured literature review in 2005 that evaluated 150 articles [11]. Six studies met their inclusion criteria. The authors noted a significant negative impact on implantation rate in the intramural fibroid group versus the control (16.4 vs 27.7%, respectively; OR: 0.62; 95% CI: ). The authors also noted a significantly lower delivery rate in the fibroid group (31.2 vs 40.9%, respectively; OR: 0.69; 95% CI: ). The investigators concluded that intramural fibroids without cavity distortion had a negative impact on pregnancy outcome in IVF/intracytoplasmic sperm injection (ICSI) cycles and myomectomy should be considered for these fibroids, particularly in patients with previously failed cycles. In 2007, Somigliana et al. [12] reported a metaana lysis of the literature on the effects of fibroids on fertility and ART outcome. Data for intramural fibroids were pooled from seven different studies and the meta-ana lysis demonstrated a statistically significant detrimental effect on both the clinical pregnancy rate with an OR of 0.8 (95% CI: ) and the delivery rate with an OR of 0.7 (95% CI: ). In 2008, Pritts et al. published an updated systematic review of the existing controlled studies on the effects of fibroids on fertility [14]. The authors evaluated 347 studies of which 23 met the inclusion criteria. They were able to confirm the previously suggested negative impact of intra mural fibroids on ART outcome with a relative risk (RR) of 0.8 (95% CI: ) for clinical pregnancy rate and RR of 0.7 (95% CI: ) for live birth rate. Pritts et al. also found that intramural fibroids were associated with an increased risk of spontaneous miscarriage with a RR of 1.7 (95% CI: ) [14]. Collectively, the results of these structured reviews and meta-analyses suggest that the discrepant findings of the initial studies on intramural fibroids were most likely due to small sample sizes and the more modest reduction in implantation and pregnancy rates with intramural fibroids (0.7) compared with submucosal fibroids (0.3). Subserosal fibroids The evidence regarding the possible effects of subserosal fibroids on reproductive outcome is consistent. Neither the original studies [62,63,69,71] nor the meta-analyses [9 14], detected any detrimental effects on ART outcome associated with subserosal fibroids. Furthermore, no beneficial effect on fertility was noted when myomectomy was performed for subserosal fibroids [72]. Management of uterine fibroids in women considering ART The two questions confronting women with fibroids who desire ART and their healthcare providers are: which fibroids should be treated and how should they be treated? From the preceding paragraphs, it is clear that intra cavity, submucosal and, in some cases, intramural fibroids should be treated before initiation of ART in order to offer the patient the best chance for success. Myomectomy has long been regarded as the standard treatment for the various symptoms associated with fibroids, such as pelvic pressure, pain or menorrhagia. Myomectomy in most cases is the best option for women who are interested in preserving their fertility [75]. Specifically regarding submucosal fibroids, Pritts et al. [14] demonstrated that, compared with infertile women with fibroids in situ, myomectomy improved the clinical pregnancy rate with the RR of 2.03 (95% CI: ). In addition, if the control group was selected as infertile women without fibroids, myomectomy appeared to return the fertility outcome to the baseline of infertile women without fibroids [14]. future science group Women's Health (2009) 5(4) 415

4 Review Ezzati, Norian & Segars One randomized trial evaluating the effects of myomectomy on fertility was reported in Casini et al. [72] randomized 181 women with a combination of submucosal, intramural and subserosal fibroids to either surgery or expectant management and reported the pregnancy rates in each subgroup following timed intercourse. The authors found that myomectomy resulted in a statistically significant higher pregnancy rate among women with submucosal fibroids (43 vs 27%), as well as those with a combination of submucosal and intramural fibroids (36 vs 15%). Concerning intramural fibroids, Bulletti and colleagues [76] reported a significant improvement in spontaneous pregnancy rate in a cohort of 106 women with fibroids of various types (i.e., submucosal, intramural and subserosal) who underwent myomectomy, compared with 106 women with fibroids who did not undergo myomectomy (42 vs 11%). The same group reported a significant improvement in pregnancy and delivery rate in IVF/ICSI cycles following myomectomy for intramural and subserosal fibroids in women with normal uterine cavity but with at least one intramural fibroid larger than 5 cm (pregnancy rate: 34% in the myomectomy group vs 15% in the group with fibroids in situ; delivery rate: 25 vs 12%, respectively) [77]. Furthermore, in the randomized clinical trial reported by Casini and colleagues [72] there was a clinically significant trend towards better pregnancy rate in the group with intramural fibroids after myomectomy (56 vs 41%), although the difference did not reach statistical significance. Based on these studies, it appears that myomectomy is beneficial and corrects the adverse reproductive outcome associated with submucosal and intramural fibroids. As with any major surgical procedure, myomectomy carries risks, such as bleeding, infection and damage to other organs. Furthermore, myomectomy is associated with adhesion formation [78,79], although this is not a concern for women who are planning to pursue ART. Another consideration is the possible impact of myomectomy on the mode of delivery in a future pregnancy. Uterine rupture during labor following myomectomy has been reported [80 82]. Despite the paucity of good quality evidence, if the myomectomy involves a transmural incision or entry into the uterine cavity, most obstetricians recommend elective caesarean delivery. In many cases with intracavity or submucosal fibroids, myomectomy can be accomplished via hysteroscopic approaches, except for larger fibroids (>4 cm). In summary, myomectomy should be considered in women affected with submucosal and/or intramural fibroids who are pursuing fertility treatments, particularly in cases of previously failed IVF/ ICSI cycles. While studies indicate better pregnancy outcomes after myomectomy for submucosal and intramural myomas, additional randomized, well-controlled studies are needed. Since pregnancy-related concerns depend on the location of the leiomyoma, the importance of an in-depth discussion regarding a management plan between patients and physicians cannot be over-emphasized. Gonadotropin-releasing hormone agonists & antagonists Gonadotropin-releasing hormone agonists have long been used to induce a transient state of hypogonadotropic hypogonadism, clinically mimicking the menopausal state. These agents work by causing a medical menopause leading to reduction in estrogen. The subsequent hypo estrogenic state can result in a rapid and significant 35 65% reduction in the fibroid size within 3 6 months [83]. Notably, gonadotropinreleasing hormone antagonists are particularly effective and can cause a 30% reduction in the size of the fibroids within 2 weeks [84,85]. Unfortunately, side effects associated with prolonged use, such as bone loss, preclude use of these agents for longer than 6 months and fibroids rapidly return to their pretreatment size upon discontinuation of treatment. Moreover, these agents inhibit ovulation and therefore are of limited use in fertility treatment, except as part of IVF/ICSI protocols. Nevertheless, for some women with fibroids, the small but notable and rapid reduction in the size of fibroids with gonadotropin-releasing hormone agonists and antagonists may prove beneficial immediately prior to ART, or preoperatively to reduce fibroid size. Uterine artery embolization Uterine artery embolization (UAE) has been developed as an alternative to myomectomy for women with symptomatic uterine fibroids who desire to avoid surgery. This therapeutic modality results in a significant reduction in the dominant fibroid size, leading to a 77 86% symptomatic relief for bleeding-related complaints within 3 months of the procedure [86]. However, fibroid size is only reduced by 40 75% [87]. Compared with myomectomy, UAE results in a shorter hospital stay, quicker recovery but higher minor complication rates after discharge [88]. In terms of major complications, UAE is similar future science group

5 Management of uterine fibroids in the patient pursuing assisted reproductive technologies Review to myomectomy [88]. A substantial concern for the application of UAE for patients considering ART is the compromising of the ovarian blood supply with the resultant adverse effect on ovarian reserve and reduction in the number of oocytes [89,90]. In addition, in some cases UAE has caused permanent endometrial atrophy [91]. Although successful pregnancies have been reported after UAE [92], most studies have reported a significantly increased risk of miscarriage as well as obstetric complications such as preterm delivery, malpresentations, intrauterine growth restriction, abnormal placentation and postpartum hemorrhage in pregnancies achieved after UAE [86 90,93,94]. One of the largest series reporting the pregnancy outcomes in 56 pregnancies after UAE suggested that in addition to increased risk of preterm delivery, caesarean section and postpartum hemorrhage, there was a significantly increased risk of miscarriage after UAE compared with the general population (30 vs 10 15%) [93]. Another study concluded that pregnancies after UAE had higher rates of preterm delivery (OR: 6.2; 95% CI: ) and malpresentation (OR: 4.3; 95% CI: ) when compared with pregnancies following laparoscopic myomectomy [94]. With these considerations in mind, it seems advisable to reserve the option of UAE for women who do not desire future pregnancy and UAE is not recommended for women pursuing ART [94,95]. MRI-guided focused ultrasound MRI-guided focused ultrasound is the newest among the emerging nonsurgical management options for symptomatic uterine fibroids [96]. In this procedure, energy from multiple elements of a phased array transducer is directed through the anterior abdominal wall resulting in coagulative necrosis of the fibroid where the ultrasound waves converge. In a recent publication reporting the 24 month follow-up data for 359 women who underwent this procedure, it was concluded that MRI-guided focused ultrasound resulted in sustained relief of fibroid symptoms, equivalent to other accepted fibroid treatments [96]. However, the maximal reduction in fibroid size at 12 months after the procedure Executive summary Introduction Uterine fibroids are present in 30 70% of reproductive-aged women. Fibroid are associated with menstrual disorders, pelvic pain, infertility and adverse obstetric outcomes. Assisted reproductive technology (ART) offers a unique opportunity to study the effects of fibroids on fertility. Classification & diagnosis Fibroids are classified as submucosal, intramural and subserosal. Submucosal fibroids are further subdivided into type 0, type I and type II. Transvaginal ultrasonography and hysterosalpingography are imaging modalities often used to evaluate uterine fibroids and/or the effects of fibroids on the uterine cavity, but hysteroscopy and saline infusion sonography are the most accurate diagnostic methods. Fibroids & infertility Submucosal and intramural fibroids clearly have an adverse effect on fertility in general and ART outcome in particular. Submucosal fibroids Submucosal fibroids (cavity distorting fibroids) adversely affect ART outcomes, resulting in reduced pregnancy and live birth rates with an odds ratio of 0.3. Altered expression of critical genes, such as HOX genes, has been implicated as the possible etiologic mechanism to explain the reduction in embryo implantation. Intramural fibroids Intramural fibroids (in the absence of cavity distortion) adversely affect ART outcomes, resulting in reduced pregnancy and live birth rates with an odds ratio of 0.7. Subserosal fibroids Subserosal fibroids do not affect ART outcome. Clinical management of uterine fibroids in women considering ART Myomectomy is the standard treatment for the symptoms associated with uterine fibroids, particularly for women who desire to preserve fertility. Myomectomy can reverse the detrimental effects of fibroids on ART outcome. Gonadotropin-releasing hormone agonists and antagonists might have some role for the treatment of uterine fibroids preoperatively. Uterine artery embolization and MRI-guided focused ultrasound surgery are alternative treatment modalities for women whose main symptoms are bleeding and/or pain, but neither is considered a first-line therapy for women pursuing assisted reproduction. future science group Women's Health (2009) 5(4) 417

6 Review Ezzati, Norian & Segars was approximately 20 25% [96]. Of note, like the UAE reports, these investigators focused on the bleeding and pain and not on fertility-related issues or pregnancy. Considering that neither the ovarian nor the endometrial blood supply should be affected during this procedure, the method may prove promising for women who seek fertility treatment. There have been case reports of pregnancies after MRI-guided focused ultrasound surgery [97,98], but, to date, there are no controlled trials to address its use for fertility indications. For most women, however, fibroid size and location will require myomectomy prior to ART. Conclusion It is clear that intra-cavitary, submucosal and intramural fibroids have an adverse effect on fertility and ART outcome. The detrimental effect of submucosal fibroids (i.e., cavity distorting fibroids) is well established. Furthermore, recent evidence suggests that intramural fibroids, even in the absence of cavity distortion, may have a negative impact on fertility at ART. Conversely, there is good evidence that subserosal fibroids do not affect ART outcomes. Myomectomy is often indicated prior to ART to normalize the uterine cavity. Although alternative treatments with a good safety and efficacy profile have become available for the management of symptomatic fibroids for indications other than infertility, myomectomy remains the treatment of choice for women seeking fertility treatment. The rising number of women who have delayed childbearing for personal reasons, together with the observed increase in the prevalence of fibroids with increasing age have led to an increased prevalence of uterine fibroids in women seeking assisted reproduction. Future perspective Future research should seek to further elucidate the mechanisms by which fibroids exert their detrimental effect on endometrium, with particular emphasis on clarifying the relative importance of fibroid size, number and proximity to the endometrium. Financial & competing interests disclosure This work was supported in part by the Program in Reproductive and Adult Endocrinology, NICHD, NIH, Bethesda, MD, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the m anuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. Bibliography Papers of special note have been highlighted as: of interest of considerable interest 1. Cramer SF, Patel A: The frequency of uterine leiomyomas. Am. J. Clin. Pathol. 94, (1990). 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9 Management of uterine fibroids in the patient pursuing assisted reproductive technologies Review 91. Tropeano G, Litwicka K, Di Stasi C, Romano D, Mancuso S: Permanent amenorrhea associated with endometrial atrophy after uterine artery embolization for symptomatic uterine fibroids. Fertil. Steril. 79, (2003). 92. Carpenter TT, Walker WJ: Pregnancy following uterine artery embolisation for symptomatic fibroids: a series of 26 completed pregnancies. BJOG 112, (2005). 93. Walker WJ, McDowell SJ: Pregnancy after uterine artery embolization for leiomyomata: a series of 56 completed pregnancies. Am. J. Obstet. Gynecol. 195, (2006). 94. Goldberg J, Pereira L: Pregnancy outcomes following treatment for fibroids: uterine fibroid embolization versus laparoscopic myomectomy. Curr. Opin. Obstet. Gynecol. 18, (2006). 95. Olive DL, Lindheim SR, Pritts EA: Non-surgical management of leiomyoma: impact on fertility. Curr. Opin. Obstet. Gynecol. 16, (2004). 96. Stewart EA, Gostout B, Rabinovici J et al.: Sustained relief of leiomyoma symptoms by using focused ultrasound surgery. Obstet. Gynecol. 110, (2007). Summary of current experience with MRI-guided focused ultrasound surgery for fibroids. 97. Rabinovici J, David M, Fukunishi H et al.: Pregnancy outcome after magnetic resonance-guided focused ultrasound surgery (MRgFUS) for conservative treatment of uterine fibroids. Fertil. Steril. (2008) (Epub ahead of print). 98. Hanstede MM, Tempany CM, Stewart EA: Focused ultrasound surgery of intramural leiomyomas may facilitate fertility: a case report. Fertil. Steril. 88, 497 (2007). Affiliations Mohammad Ezzati, MD Department of Obstetrics & Gynecology, Washington Hospital Center, Washington, DC, USA Tel.: Fax: m.ezzati@qmul.ac.uk John M Norian, MD Reproductive Biology & Medicine Branch, NICHD, NIH, Building 10, CRC, 1 East, Room , 10 Center Drive, Bethesda, MD 20892, USA Tel.: Fax: norianjo@mail.nih.gov James H Segars, MD Reproductive Biology & Medicine Branch, NICHD, NIH, Building 10, CRC, 1 East, Room , 10 Center Drive, Bethesda, MD 20892, USA Tel.: Fax: segarsj@mail.nih.gov future science group Women's Health (2009) 5(4) 421